“Cancer” generally refers to one of a group of more than 100 diseases caused by the uncontrolled, abnormal growth of cells that can spread to adjoining tissues or other parts of the body. Cancer cells can form a solid tumor, in which the cancer cells are massed together, or exist as dispersed cells, as in leukemia. Normal cells divide (reproduce) until maturation is attained and then only as necessary for replacement of damaged or dead cells. Cancer cells are often referred to as “malignant”, because they divide endlessly, eventually crowding out nearby cells and spreading to other parts of the body. The tendency of cancer cells to spread from one organ to another or from one part of the body to another distinguishes them from benign tumor cells, which overgrow but do not spread to other organs or parts of the body. Malignant cancer cells eventually metastasize and spread to other parts of the body via the bloodstream or lymphatic system, where they can multiply and form new tumors. This sort of tumor progression makes cancer a deadly disease. Although there have been great improvements in the diagnosis and treatment of cancer, many people die from cancer each year, and their deaths are typically due to metastases and cancers that are resistant to conventional therapies.
Most drug-mediated cancer therapies rely on poisons, called cytotoxic agents, selective for dividing cells. These drugs are effective, because cancer cells generally divide more frequently than normal cells. However, such drugs almost inevitably do not kill all of the cancer cells in the patient. One reason is that cancer cells can acquire mutations that confer drug resistance. Another is that not all cancer cells divide more frequently than normal cells, and slowly-dividing cancer cells can be as, or even more, insensitive to such poisons as normal cells. Some cancer cells divide slowly, because they reside in a poorly vascularized, solid tumor and are unable to generate the energy required for cell division. As a tumor grows, it requires a blood supply and, consequently, growth of new vasculature. The new vasculature that supports tumor growth is often disordered, leaving significant regions of the tumor under-vascularized and even the vascularized regions subject to intermittent blockage. These under-vascularized and blocked regions of the tumor become hypoxic—they have a lower oxygen concentration than the corresponding normal tissue, and the cells in them exhibit slower rates of division. Thus, the median oxygen concentration of only ten percent of solid tumors falls in the normal range of 40–60 mm Hg, and fifty percent of solid tumors exhibit median oxygen concentrations of less than 10 mm Hg.
In addition to rendering cytotoxic agents that target rapidly dividing cells less effective, the hypoxic environment of the tumor can lead to failures in therapy in other ways. First, oxygen is required for the therapeutic action of some cancer drug and radiation therapies. Second, cancer drugs typically reach a tumor via the bloodstream, and poor vascularization leads to poor distribution of cancer drugs to the hypoxic regions of a tumor. For all of these reasons, the hypoxic areas of the tumor represent a significant source of cancer cells resistant to therapy. Not surprisingly, then, low tumor oxygen levels are associated with a poor response to therapy, increased metastases, and poor survival.
Cancer cells require energy to support their rapid rates of cell division, and even the more slowly dividing cancer cells in the hypoxic regions of tumors require energy to survive (and the lack of oxygen deprives them of energy generation via the Krebs cycle, which requires oxygen). Not surprisingly, then, many cancer cells exhibit, relative to normal cells, increased glucose transport and glycolysis, because energy can be generated by glycolysis in the absence of oxygen. Moreover, increased uptake of glucose is one of the most common signs of a highly malignant tumor. Thus, the reference Dickens, 1943, Cancer Research 3:73, reported that “the typical intact cancer cell exhibits an unusual ability to utilize glucose by the process of anaerobic glycolysis through lactate”. Given the increased glycolysis in cancer cells, inhibition of anaerobic glycolysis by metabolic poisons such as 2-deoxy-D-glucose (also known as 2-desoxy-D-glucose and 2-DG; for synthetic methods, see Bergmann, 1922, Deutsch. Chem. Ges. 56:158–60; Cramer, 1952, Franklin Inst. 253:277–80; and Japan patent publication No. 54-041384) has been studied as a means to kill cancer cells preferentially (see McDonald, 1952, Cancer Research 351–353).
2-DG has been reported to inhibit glycolysis in and growth of cancer cells (see Woodward, 1954, Cancer Res. 14:599–605; Barban, 1961, J. Biol. Chem., 236(7):1887–90; Myers, March 1975, Biochem Biophys Res Commun. 63(1):164–71; Steiner, July 1983, Cancer Lett. 19(3):333–42; Karczmar, January 1992, Cancer Res. 52(1):71–76; Kern, August 1987, surgery 102(2):380–85; Kaplan, February 1990, Cancer Res. 50(3):544–51; Kaplan, March 1991, Cancer Res. 51:1638–44; Haberkorn, November 1992, J. Nucl. Med. 33(11):1981–87; Jha, April 1993, Int. J. Radiat. Biol. 63(4):459–67; Malaisse, March 1998, Cancer Lett. 125:4549; and Aft et al., 2002, Br. J. Cancer 87: 805–812). 2-DG has also been reported to retard tumor growth in some animal models (Sokoloff, 1955, A.M.A. Arch. Path. 729–732; Ball, 1957, Cancer Res. 17:235–39; Laszlo, February 1960, J. Natl. Canc. Inst. 24(2):267–281; Dills, November 1984, J. Nutr. 114(11):2097–106; Kern, 1987, Surgery 102(2): 380–385; and Cay et al., 1992, Cancer Res. 52(20): 5794–5796). 2-DG was first administered to human cancer patients in the 1950s (see Landau, 1958, J. Natl. Canc. Inst. 21:485–494) by single i.v. infusion without any apparent therapeutic effect.
2-DG has been studied in combination with radiation (see Purohit, March 1982, Int. J. Radiat. Oncol. Biol. Phys. 8:495–99; Tannock, March 1983, Cancer Res., 43(3):980–83; Jain, May 1985, Int. J. Radiat. Oncol. Biol. Phys. 11(5):943–50; Gridley, 1985, Oncology 42(6):391–98; Dwarakanath, May 1987, Int. J. Radiat. Oncol. Biol. Phys. 13(5):741–46; Dwarakanath, March 1999, Int. J. Radiat. Oncol. Biol. Phys. 43(5):1125–33; Dwarkanath, July 2001, Int. J. Radiat. Oncol. Biol. Phys. 50(4):1051–61; Kalia, April 1993, Indian J. Exp. Biol. 31(4):312–15; Latz, July 1993, Strahlenther Onkol 169(7): 405–11; Mohanti, April 1996, Int. J Radiat. Oncol. Biol. Phys. 35(1):103–11; Kalia, May 1999, Indian J. Med. Res. 109:182–87; and Yeung, 11 Dec. 2001, PCT WO 02/58741).
2-DG has been studied in combination with other cytotoxins and anti-cancer drugs (see Lampidis, February 1983, Cancer Res. 43:716–20; Bernal, October 1983, Science 222:169–72; Herr, April 1988, Cancer Res. 48:2061–63; Liu, May 2001, Biochemistry, 840(18):5542–47; Saydjari, July 1989, Invest. New Drugs 7:131–38; Saydjari, 1989, Pancreas, 4:38–43; Haga, March 1998, Int. J. Cancer 76(1):86–90; Belfi, April 1999, Biochem. Biophys. Res. Commun. 257(2):361–68; Yamada, 1999, Cancer Chemother. Pharmacol. 44(1):59–64; Halicka, January 1995, Cancer Res. 55(2):444–49; Yun, 1995, Oncol. Res. 7(12):583–90; Schaider, 1995, J. Cancer Res. Clin. Oncol. 121(4):203–10; Ben-Horin, July 1995, Cancer Res. 55(13):2814–21; Tomida, November 1996, Inter J. Cancer Res 68(3):391–96; Reinhold, September 2000, Oncol. Rep., 7(5):1093–97; Mese, March 2001, Anticancer Res. 21:1029–33; Lampidis, 2 Mar. 2001, PCT WO 01/82926 and U.S. Pat. No. 6,670,330).
However, after more than five decades of study, 2-DG has not been approved for the treatment of cancer in the United States or Europe. There remains a need for methods of treating cancer with 2-DG. The present invention meets that and other needs.